ES2659320T3 - Remineralization of teeth - Google Patents

Abstract

A film for use in an oral cavity in which said film is produced from an aqueous mixture of its components and comprises: a water-soluble polymeric film former that is an edible non-ionic cellulose derivative selected from any one or a combination of methylcelluloses, hydroxypropylmethyl cellulose, hydroxyethylcellulose, hydroxypropyl cellulose and carboxymethyl cellulose; and a bioactive glass comprising 40-80% by weight of silicon dioxide (SiO2), 0-35% by weight of sodium oxide (Na2O), 4-46% by weight of calcium oxide (CaO) and about 1 -15% by weight phosphorus oxide (P2O5); and wherein the bioactive glass is added to a solution of the polymeric film former to form the aqueous mixture and the bioactive glass is maintained in this aqueous environment for no more than 1-120 hours or more preferably 1-60 hours before the water content is reduced by 5-70% by weight so as to minimize adverse reactions between the polymeric film former and the bioactive glass.

Description

DESCRIPTION

Remineralization of teeth

Field of the Invention

The present invention relates to a film and a method for the use of a film for remineralization of teeth. More particularly, the present invention relates to a film comprising a bioactive glass and a water soluble polymer and to a method for using said film for remineralization of teeth.

Background of the invention

It is well known that the structure of the teeth comprises an internal dentin layer and an external hard enamel layer, which serves to protect the teeth. The enamel layer is composed of dense mineral crystals of dense hydroxyapatite; in the form of large "prismatic" enamel crystals surrounded by smaller crystals that fill the "inter-prismatic" spaces. The formula of calcium hydroxyapatite is nominally Ca5 (PO4) 3OH. However, dentin is composed of both hydroxyapatite, as well as structural proteins that result in a much softer and less dense structure than enamel, and which is much easier to damage. The dentin structure also consists of pores or "tubules" that create openings from the surface of the teeth 15 running down into the pulp cavity of the teeth, where the nerve of the teeth is located. Normally this softer porous dentin structure is covered by the densest enamel layer, or by the soft gingival tissue, which protects the nerve from external stimuli. The hypersensitivity of the teeth is associated with the exposure of these tubules, through the loss of the protective enamel layer or recession of the gums, which tends to increase with age. The recession of the gums can also be caused by over-brushing, 20 as well as periodontal disease. The loss of enamel can occur as a result of erosion by acidic foods or cariogenic bacteria and abrasion by over-brushing or other mechanical effects. Those who use orthodontic appliances are also especially susceptible to loss of tooth enamel, leading to white spot lesions.

Demineralization of tooth enamel tends to reveal tubules. The dentinal tubules are naturally present in the enamel, and provide an osmotic flow of fluid between the region of the inner pulp of the teeth and the outer root surface. However, when demineralization of the enamel layer occurs, these tubules tend to be exposed. When heat, cold or pressure is applied, fluids tend to gain direct access to the nerve of the tooth, causing pain. It is possible to alleviate this condition by coating the tooth with varnishes, lacquers, etc., but this tends to be a short-term remedy, since the lacquers wear out very quickly. 30

Bioactive glasses, alone or incorporated into oral care compositions, are known to remineralize teeth. When applied to the teeth they have the effect of rebuilding the hydroxy apatite structure. For example, US Patents 6,338,751 and 6,086,374, refer to oral care products comprising remineralization compositions (normally comprising calcium, phosphorus, silica and sodium ions in the form of bioactive glass). The bioactive glass incorporated in these products releases remineralizing ions 35 on the surface of the teeth, and helps occlude the open tubules, reducing the sensitivity of the teeth, and reconstructing the enamel layer. However, a disadvantage of these compositions is that the contact time with toothpastes or toothpastes is limited to the brushing time, and this may be only a minute or two.

US Patent No. 6,365,132 and International Publication WO 99/13852, detail procedures for teeth whitening, contacting the surface of the teeth with an effective amount of bioactive particulate glass. However, the defined compositions are not discrete (for example, notably) and are not suitable for use in all situations.

US Patent No. 6,190,643, incorporated herein by reference, describes a method for reducing the viability of harmful oral microorganisms and for whitening teeth 45 by treatment with bioactive glass.

Patent Publication WO 02/49578 of Henkel Corporation (corresponding to US2003 / 0219388), incorporated herein by reference, describes a water soluble or water expandable film containing several soluble calcium salts for remineralization of teeth. However, these salts are "poorly soluble" in water and hydroxyapatite is previously formed in the film, resulting in the limited ability to remineralize the surface of the teeth.

In addition, many prior art documents are based on the use of bioactive glasses in water-based systems, due to their inherent bioactivity. For example, we refer to Chapter 3 of “Introduction to Bioceramics” by L. L Hench and J. Wilson, incorporated into the present invention as a reference, which states that alkaline species in glass can be depleted in a few minutes of exposure an aqueous solution 55

Additionally, International Publication WO 2006/055317, describes dental compositions that release calcium and phosphorus in the oral cavity for a sustained period. These products have been constructed to remain on the surface of the teeth for a number of months, and can be prepared from polymerizable materials that harden on the surface of the teeth. Other compositions are prepared from solvent-based formulations (ethanol). 5

It is an object of at least one aspect of the present invention to eliminate or mitigate at least one or more of the aforementioned problems.

It is a further object of at least one aspect of the present invention to provide a film with the ability to remineralize the teeth.

It is a further object of at least one aspect of the present invention to provide a method for remineralization of teeth using a film.

Summary of the invention

According to a first aspect of the present invention a film is provided for use in an oral cavity, said film comprising:

a water soluble polymeric film former; and 15

a bioactive glass.

According to a second aspect of the present invention, a film is provided for use in an oral cavity, said film comprising:

a water soluble polymeric film former; Y

a bioactive glass; twenty

in which the film has the ability to adhere to at least one tooth in the oral cavity for a maximum time of approximately 60 minutes before the film dissolves or substantially dissolves and in which the film has the ability to carry out the remineralization of the teeth.

In accordance with a third aspect of the present invention a film is provided for use in an oral cavity, said film comprising:

a water soluble polymeric film former; Y

a bioactive glass;

wherein the film has the ability to dissolve or at least substantially dissolve in a maximum time of approximately 60 minutes and in which said film has the ability to carry out remineralization of the teeth. 30

Normally, the film may have the ability to perform remineralization of the teeth at the time of application to a tooth, or a number of teeth. Generally speaking, the present invention may reside in the provision of a remineralization composition comprising a bioactive glass in the form of a thin film, which can adhere to one or more teeth, and provides a convenient and discrete method for generating a concentration. high and sustained local remineralizing components on the surface of a tooth. 35

When hydrated, the film of the present invention can release remineralizing ions that form, for example, a stable crystalline hydroxy apatite carbonate layer on the surface of a tooth, providing long-term reduction in tooth sensitivity.

The film can also comprise a naturally derived film former that, for example, can be chemically modified. For example, the chemically modified film former naturally derived may be any suitable water soluble polymer, although preferably a naturally derived nonionic cellulose derivative, such as hydroxypropyl cellulose which allows a pH range of between about 6, 0 and 11.0, between about 7.0 and 10.5 or preferably between about 7.5 and 9.5, which is optimal for the formation of hydroxycarbonate apartite ore.

It has also been conveniently discovered that the film of the present invention preferably sticks to the teeth without sticking to the soft tissue inside the mouth. Without being limited to any theory, the water-soluble polymeric film former, such as hydroxypropyl cellulose, can be classified as an active surface polymer. The water-based solutions of the water-soluble polymeric film former can show interfacial and surface tension greatly reduced. The hydrated layers of the water-soluble polymeric film former can effectively lubricate the soft tissue within a mouth, thereby allowing the water-soluble polymeric film former to easily slide, for example, into the interior of the lip.

The film of the present invention can also be extremely useful since the film has the ability to accumulate and hydrate around orthodontic appliances by providing a high concentration of ions required to help generate hydroxy carbonate apatite at the necessary point.

By "water soluble" in the present invention in reference to the water soluble polymeric film former means any polymeric material that forms a colloidal solution or solution, in which the approximate volume in solvent in millimeters per gram of solute, is within the range. from about 0.01 to 10,000.

The bioactive glass, for example, may be a particulate glass that may have the ability to release a remineralization composition. The bioactive glass may be an inorganic glass that has a silicon oxide as its main component, and that may have the ability to bind with growth tissue when in contact with physiological fluids. The bioactive glass contains the essential ions, for example, calcium and phosphorus and as the saliva dissolves the film (for example a strip) these ions are released to help form hydroxy carbonate apatite in the teeth. Therefore the film may comprise: calcium; match; silica and / or sodium atoms and / or ions or any combination thereof, in the form of a bioactive glass.

The film can form a layer of hydroxycarbonate apatite in vitro, when placed in the body fluid or a simulated body fluid. Conveniently, the film does not activate any significant adverse immune responses in the body, such as in the oral cavity.

The film comprises a water-soluble polymeric film former in an amount of about 1-90% by weight, about 20-80% by weight, about 30-70% by weight, about 40-80% by weight or about 50-60% by weight. Alternatively, the film may comprise a water soluble polymeric film former in an amount of at least about 10% by weight, at least about 30% by weight, at least about 50% by weight, at least about 70% by weight or at least about 90% by weight.

The film may comprise bioactive glass in an amount of approximately 10-90% by weight, approximately 20-80% by weight, approximately 30-70% by weight, approximately 40-80% by weight or approximately 50- 60% by weight. Alternatively, the film may comprise bioactive glass in an amount of at least about 10% by weight, about 30% by weight, about 50% by weight, about 70% by weight or about 90% by weight . Generally speaking, the particulate glass may comprise about 1-60%, about 1-30%, typically about 2-25%, especially about 5-20%, and notably approximately 8-16% by weight of the film. 30

A typical composition for the film is approximately 40-80% by weight silicon dioxide (SiO2), approximately 0-35% by weight sodium oxide (Na2O), approximately 4-46% by weight calcium oxide (CaO) and about 1-15% by weight of phosphorus oxide (P2O5). When made by a traditional glass smelting process, the preferred ranges may be:

about 40-60% by weight of silica; 35

about 10-30% by weight sodium oxide;

about 10-30% by weight calcium oxide; Y

approximately 2-8% by weight phosphorus oxide.

In particular embodiments, the water-soluble polymeric film former can be manufactured from a polymer having an average molecular weight range of about 1,000-1,500,000, about 1,000,000-500,000, about 50,000-500,000, about 100,000-200,000. , about 1,000 - 100,000, about 1,000 - 50,000, about 1,000 - 20,000 or about 10,000 - 20,000. Preferably, the average molecular weight may be about 50,000-250,000 or more preferably about 140,000. The average molecular weight can be determined by size exclusion chromatography. Four. Five

Just as it provides a matrix for bioactive glass, silica can act as an abrasive when a gelatinized film is removed from the teeth by brushing.

Bioactive glass can be made through a traditional glass smelting process (when sodium oxide is normally present) or by a precipitation or gelatinization process called a "sol-gel" procedure in the prior art (when it may be absent sodium oxide). Other components such as calcium fluoride, boron oxide, aluminum oxide, magnesium oxide and potassium oxide may also be included.

The bioactive glass may be a calcium and phosphorus release glass that includes for example calcium and phosphorus in a glass that preferably allows them to be released when placed in the oral environment. Such glasses have been described in the literature as "remineralizing" or, with respect to medical applications, "bioactive". Said 55 glasses can be derived from cast iron or sol-gel. Such glasses may also be amorphous or include one or more crystalline phases (ie partially crystalline, sometimes described as "ceramic-glass").

Remineralizing or bioactive glasses are well known to those skilled in the art and typical glasses are described, for example in US Pat. Nos. 4,698,318 (Vogel et al), 5,074,916 (Hench et al), 5,162,267 (Smyth), 5,296,026 (Monroe et al), 6,338,751 (Litkowski et al) and 6,709,744 (Day et al) and American Patent Application Publications No. 2003/0167967 (Narhi et al), 2004 / 0241238 (Sepulveda et al) and 2004/0065228 (Kessler et al). Exemplary remineralizing or bioactive glasses are available, for example, of 5 NovaMin (US) under their trade names and also under the trade names of CERABONE A / W from Nippon Electric Glass Co., Ltd. (Shiga, Japan), BIOVERIT as Vogel describes in Introduction to Bioceramics, LL Hench and J. Wilson, eds., World Scientific Publishing (1993), 45S5 and 45S5F as described by Hench and Andersson in Introduction of Bioceramics, LL Hench and J. Wilson, eds., World Scientific Publishing (1993). The bioactive release glass may not include high levels of aluminum oxide (for example alumina), which is known to hamper bone patch in medical applications. Such glasses without high levels of aluminum oxide may include less than about 5%, and sometimes less than about 3%, 2%, or even about 1% by weight of aluminum oxide. In contrast, ionomer glass compositions generally depend on a sufficiently high level of leachable aluminum ions for the ionomeric crosslinking reaction, typically 10-45% by weight of AI2O3. fifteen

In some embodiments, the bioactive glass may include from about 35% to 60% by weight of silica, and preferably about 40% to 60% by weight of silica. In some embodiments, the bioactive glass includes less than about 20%, and sometimes less than about 15%, 10%, 5%, 3%, or even 1% by weight of silica.

In some embodiments, the bioactive glass may include at least about 15%, and sometimes at least 20, about 20%, 25%, 30%, 35%, or even 40% by weight of pentoxide. phosphorus (P2O5). In such embodiments, the bioactive release glass may include at most about 80%, and sometimes at most about 75%, 70%, 65%, 60%, 55%, 50%, 45 %, or even about 40% by weight of phosphorus pentoxide (P2O5).

The bioactive glass may include less than about 20%, and sometimes less than about 25%, 12%, 8%, or even about 6% by weight phosphorus pentoxide (P2O5). In such embodiments, the bioactive glass includes at least about 1%, and sometimes at least about 2%, or even about 3% by weight of phosphorus pentoxide (P2O5).

In some embodiments, the bioactive glass may include at least about 10%, and sometimes at least about 15%, 20%, 25%, or even about 30% by weight calcium oxide. In said embodiments, the bioactive glass may include at most about 70%, and sometimes at most about 60%, 50%, 40%, or even about 35% by weight calcium oxide.

The bioactive glass optionally includes at most about 25%, and sometimes at most about 20%, 15%, 10%, or even about 5% by weight of fluoride.

In some embodiments, the bioactive glass optionally includes at most about 60%, and sometimes at most about 55%, 50%, 45%, 40%, 35%, or even about 30% in weight of SrO, MgO, BaO, ZnO, or combinations thereof. In some embodiments, the bioactive glass optionally includes at least about 0.5%, and sometimes at least about 1%, 5%, 10%, 15%, or even 20% by weight of SrO, MgO, BaO, ZnO, or combinations thereof. The bioactive glass optionally includes at most about 40%, and sometimes at most about 35%, 30%, 25%, 20%, 15%, 10%, or even about 5% in Rare earth oxide weight. The bioactive glass optionally includes at most about 45%, and sometimes at most about 40%, 30%, 20%, 10%, 8%, 6%, 4%, 3%, or even about 2% by weight of Li2O, Na2O, K2O, or combinations thereof. Four. Five

The bioactive glass optionally includes at most about 40%, and sometimes at most about 30%, 25%, 20%, 15%, 10%, or even about 5% by weight of B2O3.

The bioactive glass may include less than about 15%, and sometimes less than about 10%, 5%, or even about 2% by weight of ZrO2.

The bioactive glass may include approximately 40-60% by weight of SiO2, approximately 10-35% by weight of CaO, approximately 1-20% by weight of P2O5, approximately 0-35% by weight of Na2O and less than about 5% by weight of AI2O3.

The bioactive glass may include about 10-70% by weight of CaO; approximately 20-60% by weight of P2O5; less than about 3% by weight of AI2O3; about 0-50% by weight of SrO, MgO, BaO, ZnO, or combinations thereof; and less than about 10% by weight of Li2O, 55 Na2O and K2O combined.

The bioactive glass may include about 10-70% by weight of CaO; approximately 20-50% by weight of P2O5; less than about 3% by weight of AI2O3; about 0-50% by weight of SrO, MgO, BaO, ZnO, or combinations thereof; and less than about 10% by weight of Li2O, Na2O and K2O combined.

The bioactive glass may include about 10-50% by weight of CaO, at least 15% and less than about 50% by weight of P2O5, less than about 3% by weight of AI2O3, less than about 10% by weight of Li2O, Na2O, and K2O combined, and about 0-60% by weight of SrO, MgO, BaO, ZnO, or combinations thereof.

The glass can be in a variety of finely divided forms including particles, fibers or platelets. The preferred average particle size for dental and orthodontic applications is less than about 50 micrometers, more preferably less than about 10 micrometers, more preferably less than about 3 micrometers. Nanoscale sizes are also highly preferred (for example less than about 0.5 micrometers). Combinations of intervals of different sizes can also be used.

The bioactive glass may optionally be surface treated (for example, with silane; acid or methacrylate acid or other polymers, monomers, oligomers, etc.) as described below. Said surface treatments can result, for example, in the improved binding of particles to the matrix. Preferably, the glass is treated on the surface by procedures similar to those described, for example, in US Patent No. 5,332,429 (Mitra). In synthesis, the glass can be treated on the surface by combining the glass with one or more liquids that have dissolved, dispersed or suspended therein an agent to treat the surface (for example, fluoride ion precursors, silanes, titanates, etc. .). Optionally, the one or more liquids include water, and if an aqueous liquid is used, it may be acidic or basic. Once treated, at least a part of the one or more liquids can be removed from the surface treated glass, using any convenient technique (for example, spray drying, oven drying, opening drying, lyophilization and combinations thereof) . See, for example, US Patent No. 5,980,697 (KoIb et al) for a description of gap drying. In one embodiment, the treated glass can be oven dried, typically at 25 drying temperatures from about 30 ° C to about 100 ° C, for example, overnight. The surface treated glass can be heated additionally, as desired. The treated and dried glass can subsequently be cast or lightly ground to break up the agglomerates.

Normally, the average particle size of the bioactive glass can have an effect on the ion release range when in contact with water and can usually be less than about 100 micrometers, about 75 micrometers, about 50 micrometers, about 20 micrometers, normally less than about 10 micrometers, and often less than about 5 micrometers. Alternatively, the average particle size of the bioactive glass can range from about 0.01-200 microns; about 0.01-50 micrometers; about 0.01-20 micrometers; about 0.1-10 micrometers; or about 0.1-5 micrometers. 35

In particular embodiments, the 50th percentile diameter of the bioactive glass may normally be in the range of about 2-20 micrometers; or for example, about 5-10 micrometers. Suitable bioactive glasses are available under the trademark of NovaMin®, although other bioactive glasses can be used.

The bioactive glass can be mixed with other materials such as any one or a combination of the following: sweeteners; flavorings; antimicrobial agents; plasticizing agents; coloring agents; agents that stimulate saliva; cooling agents; surfactants; stabilizing agents; emulsion agents; thickening agents; conservatives; volume generating agents; humectants; vitamins; minerals; chlorides; and loads.

The film may be in the form of a thin strip suitable for oral consumption. Four. Five

The film, preferably in the form of a strip, is projected to expand or dissolve in the oral cavity releasing the remineralization composition over a period of time. The film is projected to be adhered to the surface of a tooth, either through its own properties, or using an adhesive. The particulate glass in the strip can be provided in a single layer, incorporated in one or more layers of a multilayer product or alternatively it can simply be deposited on the surface of a film former strip 50 (preferably of a dispersible edible material in water)

Normally, the film can be a strip, in which the strip can be substantially rectangular in shape, although any form of strip can be used (for example substantially rounded rectangle, substantially oval, substantially square, substantially circular). The strip may have a minimum thickness of approximately 10 µm to allow ease of handling. The strip may have a preferred maximum thickness of about 500 µm or more preferably about 200 µm, so that the physical dimensions of the strip do not prevent the body from dissolving in a desired period of time in an oral cavity for example by means of the saliva action Generally the thickness of the strip may be within the range of

approximately 20 to 100 μm, and more normally approximately 40 to 80 μm.

The width of the strip may be about 0.05-5 cm or preferably about 1-2.5 cm, and the length may be about 0.05-10 cm or preferably about 4-8 cm.

In general, the strip may be designed for application to one or more teeth, although smaller pieces may be incorporated into other products (e.g., toothpastes, toothpastes, etc.). 5

The strip may be dry, so it is understood that the strip is dry at the time of contact. However, the strip may contain about 1 to 20% by weight, or about 1 to 15% by weight, of wastewater, which remains after the manufacturing process. When dry, the film effectively adheres to the tooth (absorbing water from the surface of the tooth and oral cavity), and is thus anchored in place for a period of time. This helps provide a long contact time (in comparison, for example, 10 with toothpastes).

The strip can dissolve rapidly in water / saliva in the oral cavity. By "rapid dissolution", it is understood that the water-soluble components (eg, water-soluble polymeric film former) of the strip is preferably dissolved, or substantially dissolved in a time of about 1 to 30 minutes, about 5 to 20 minutes, about 5 to 15 minutes or about 5 to 10 minutes. 15 Normally the time for dissolution of a strip in an oral cavity may be approximately 60 minutes maximum, and the minimum time may be approximately 1 second. Generally, the strip dissolves substantially in about 10 seconds to about 10 minutes. Within this time, the release of a substantial part of the remineralization composition comprising the bioactive glass will have occurred. twenty

The film is generally formed of edible material. By "edible material" is meant a material that has the ability to be consumed by a user. Normally, this is a material approved for use by the appropriate regulatory authorities.

The strip is formed from any suitable edible water-soluble polymeric material, such as any or a combination of the following: methyl celluloses (for example sodium carboxymethyl cellulose), hydroxypropylmethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, carboxymethyl cellulose. Any suitable combination of the above compounds, such as a mixture of two, three, four or more of the materials may be employed. In addition, the different layers in a strip of multiple layers may comprise different combinations of materials.

It is preferable to use a non-ionic film former, such as a cellulose derivative (for example, hydroxypropyl cellulose, hydroxypropyl methylcellulose and the like). The non-ionic nature of the film former prevents unwanted reaction with the remineralization composition.

In use, the film hydrates and absorbs water and expands, thereby allowing the release of remineralization ions from the film on the surface of the teeth. The film former may simply expand, but remain essentially intact for subsequent removal, or the film former may dissolve or disperse in the saliva within the oral cavity.

The remineralization composition itself has been found to exhibit useful antimicrobial properties. However, the strip can also comprise antimicrobial agents (for example, bactericides) in any suitable form. Antimicrobial agents may be present in an amount up to the maximum levels allowed by the appropriate regulatory authorities. For example, any one or one combination of the following antimicrobial agents can be used; triclosan; cetyl pyridinium chloride (CPC); domifen bromide; quaternary ammonium salts; sanguinarine; suitable fluorides; alexidine; octonidine; and EDTA.

Flavors may also be included. Suitable flavorings may exhibit fragrant properties. Suitable flavorings may be added during the manufacturing process in the form of flavored oils. Flavors may form amounts of about 0-30% by weight or about 0-10% by weight of the film.

Flavors can be chosen from natural oils, synthetic flavored oils, aromatic flavors, oil resins and extracts derived from plants, leaves, flowers, fruits, etc. and combinations thereof.

Flavored oils that can be used include any of or a combination of the following: spearmint oil; cinnamon oil; peppermint oil; clove oil; Bay oil; thyme oil; 50 cedar leaf oil; nutmeg oil; sage oil; and bitter almond oil.

Also useful are artificial, natural or synthetic fruit flavors such as vanilla, chocolate, coffee, cocoa and citrus oil, including lemon, orange, grape, lime and grapefruit and fruit essences including apple, pear, peach, strawberry, raspberry, cherry, blackberry, pineapple, peach, etc. These flavorings can be used individually or in a mixture. Commonly used flavors include mints, such as peppermint, artificial vanilla, derivatives 55

of cinnamon and various fruit flavors, whether used individually or mixed in additions. Flavors such as aldehydes and esters include cinnamyl acetate, cinnamaldehyde, citral, diethylacetal, dihydrocarbyl acetate, eugenyl format and p-methylanisol, etc. They can also be used.

Additional examples of aldehyde flavors include but are not limited to any of, or a combination of the following: acetaldehyde (apple); benzaldehyde (cherry, almond); cinnamic aldehyde 5 (cinnamon); citral, for example alpha citral (lemon, lime); neral, for example beta citral (lemon, lime); decanal (orange, lemon), ethyl vanilla (vanilla, cream); heliotropin, for example, piperonal (vanilla, cream); vanilla (vanilla, cream); alpha-amyl cinnamaldehyde (aromatic fruit flavors); butyraldehyde (butter, cheese); valeraldehyde (butter, cheese); citronella; decanal (citrus fruits); C-8 aldehyde (citrus fruits); C-9 aldehyde (citrus fruits); C-12 aldehyde (citrus fruits); 2-ethyl butyraldehyde (berry fruits); hexanal, that is trans-2 (berry fruits); 10 tolyl aldehyde (cherry, almond); veratraldehyde (vanilla); 2,6-dimethyloctanal (green fruit); and 2-dodecenal (citric, tangerine); Cherry; grape; mixtures thereof and the like.

As required, the film may comprise a sweetening agent or a combination of sweetening agents. The sweetening agents may be present in an amount less than about 30% by weight, although more usually less than about 20% by weight. fifteen

Typical sweeteners include monosaccharides, disaccharides and polysaccharides such as any of one or a combination of the following: xylose; ribose; glucose (dextrose); mannose; galactose; fructose (for example, levulose); sucrose (for example, sugar); and maltose; an invert sugar (for example a mixture of fructose and glucose derived from sucrose); partially hydrolyzed starch; corn syrup solids; dihydrocalconas; monelina; steviosides; and glycyrrhizine. twenty

In addition, water soluble artificial sweeteners such as soluble saccharin salts can be used. For example, any of, or a combination of the following artificial sweeteners can be used: sodium or calcium saccharin salts; cyclamate salts; sodium, ammonium or calcium salts of 3,4-dihydro-6-methyl-1,2,3-oxathiazine-4-one-2,2-dioxide; 3,4-dihydro-6-methyl-1,2,3-oxathiazine-4-one-2,2-dioxide (acesulfame-K) potassium salts; sacralose; and the saccharin form of free acid. 25

In addition, dipeptide-based sweeteners such as any of, or a combination of the following: sweeteners derived from L-aspartic acid, such as L-aspartyl-L-phenylalanine methyl ester (aspartame); L-alpha-aspartyl-N- (2,2,4,4-tetramethyl-3-thienyl) -D-alaninamide hydrate; methyl esters of L-aspartyl-L-phenylglycerin and L-aspartyl-L-2,5-dihydrophenyl-glycine; L-aspartyl-2,5-dihydro-L-phenylalanine; and L-aspartyl-L- (1-cyclohexien) -alanine. 30

Water soluble sweeteners derived from naturally occurring water soluble sweeteners such as a chlorinated ordinary sugar derivative (sucrose) may also be used.

Additionally, protein based sweeteners such as thaumatoccous danielli (for example, Thaumatin I and II) can be used.

Plasticizing agents can also be used. The plasticizing agents may be present in an amount of about 0% to 25% by weight or about 0% to 15% by weight of the film. For example, plasticizing agents such as triacetin, monoacetin, diacetin and polyols can be used for example, glycerol, sorbitol and mannitol.

Normally, the manufacturing process for forming the film may involve dispersing the active glass in a polymer solution containing all the other ingredients. Alternatively, the solvent can be omitted if a suitable heat smelting process is used.

It is surprising that the film of the present invention can be produced from an aqueous mixture of its components. The previous expectation was that in the aqueous mixture, the particulate glass may release ions prematurely, which may form hydroxyapatite in the film. In addition, it has been surprisingly discovered that the aqueous production environment does not significantly denigrate the bioactivity of the bioactive glass; giving the opportunity to avoid long processing times.

The proportion of solvent to the particulate glass and other ingredients can be altered during processing to obtain the proper viscosity for film formation. The resulting liquid can be made homogeneously by suitable mixing and the stepwise addition of the water-soluble polymeric film forming material. Subsequently, a film can be formed using suitable procedures, wherein the liquid obtained containing the bioactive glass can be deposited (for example, by extrusion) or other techniques that form films known to those skilled in the art, on the conveyor paper or a continuous band, which can be used as a support, as the wet film is transported in a dryer. The support material of the film can be a polymeric film or paper although preferably it is a craft paper coated with low density polyethylene. 55

To avoid adverse reactions, it is preferred to minimize the time between the formation of the aqueous solution / suspension and the formation of the film.

The dryer may comprise a tempered air tunnel with low humidity or use other heat sources, such as Infrared (IR) lamps to evaporate the solvent and form a dry coil. Alternatively, the film can be melted into sheets and dried in an oven. Normally, the maximum air temperature in a dryer or oven, 5 may be approximately 100 ° C, and the minimum temperature may be approximately 20 ° C. Preferably, the maximum air temperature in a dryer or oven may be approximately 80 ° C and the minimum temperature may be 30 ° C.

The resulting film may be cut and packed directly or stored on a reel or sheet format, for future processing. 10

The mixture containing the bioactive glass, the solvent and the water-soluble edible polymeric material can be dried to form a laminar body, and subsequently formed into a strip using conventional techniques.

In terms of supplying a remineralization composition, a strip will normally contain from about 1 to 100 mg, from about 1 to 50 mg, from about 1 to 20 mg or from about 1 to 10 mg of bioactive glass per tooth or, for example , or about 1 to 100 to 15 mg or about 3 to 30 mg within a film to be used on multiple teeth. A particular benefit of the film is that it allows the teeth to be completely covered with a uniform or substantially uniform layer of remineralization material.

The film may also contain other remineralization agents, such as fluoride or other agents that release calcium and phosphorus that may be available for remineralization of teeth, for example, during the attack of an acid from the surface of the tooth. Examples of other remineralizing agents may include, but are not limited to any, or a combination of the following: sodium fluoride (NaF); sodium monofluorophosphate (MFP); stannous fluoride, amorphous calcium phosphate (ACP); Casein phosphopeptide (Recaldent®) or other soluble calcium phosphate compositions.

The film can also be used for the prevention and treatment of gingivitis (gum disease) and 25 caries at the root, and it has been shown to inhibit the growth of oral bacteria associated with the development of caries and periodontal disease. A particular source of tooth demineralization is associated with the wear of orthodontic appliances, where the contact between the tooth and the (usually metal) apparatus leads to erosion of tooth enamel, creating interfaces where cariogenic bacteria can live . Demineralized areas are referred to as "white spot lesions" because demineralized varnish 30 is much whiter than the surrounding varnish. The film of the present invention can be used with a prophylactic or therapeutic capacity.

In accordance with a fourth aspect of the present invention, a dental composition is provided for use in the oral cavity, said dental composition comprising:

a water soluble polymeric film former; and 35

a bioactive glass.

The water soluble polymeric film former and the bioactive glass can be as indicated above.

Normally, the dental composition may be in the form of a film (for example a strip). In accordance with a fifth aspect of the present invention, a film is provided for use in the oral cavity for remineralization of the teeth, comprising:

a water soluble polymeric film former; Y

a particulate glass comprising calcium oxide, silicon oxide and / or phosphorus oxide, which releases ionic portions of phosphorus and calcium in contact with water and is effective in producing crystalline hydroxyapatite in a tooth.

Particle glass is a bioactive glass.

The water soluble polymeric film former and the bioactive glass may be as defined above. Four. Five

In accordance with the seventh aspect of the present invention, there is provided a method for forming a film for use in the oral cavity and with the ability to carry out remineralization of the teeth, said procedure comprising:

provide a water soluble polymeric film former; Y

provide a bioactive glass; fifty

mix the water soluble polymeric film former and the bioactive glass; Y

in which the mixture of the water soluble polymeric film former and the bioactive glass has the ability to form into a film with the ability to carry out remineralization of the teeth.

Normally, the film can be as defined in the first aspect of the present invention. The water soluble polymeric film former and the bioactive glass can therefore be as defined above.

The process may comprise adding the bioactive glass to an aqueous mixture containing a water soluble polymer. This mixture may also contain plasticizers, humectants, flavorings, emulsifiers, fillers, sweeteners and colors or combinations thereof.

Subsequently a resulting liquid mixture can be passed through a high shear mixer to produce a homogeneous dispersion which in turn can be deaerated before being coated on a conveyor paper and dried with air at a temperature higher than that of the environment, not exceeding, for example, approximately 60 ° C. 10

Without intending to limit itself to any theory, the point of addition of bioactive glass to the polymer solution is considered as important since adding it after the polymer limits the amount of free water in the system. The bioactive glass can be kept in this environment for about 1 to 120 hours or more preferably about 1 to 60 hours before the water content is reduced to about 5% to 70%, 5% to 50%, about 5% to 25 % or about 20% or about 10% by weight. At this point the water activity of the dry film is usually below about, for example, 0.8, and usually below about 0.6.

The unexpected and surprising result is that the bioactive glass remains relatively intact during the manufacturing process, maintaining a high level of reactivity through the finished product. The preservation of reactivity is demonstrated through a rise in pH, when the films dissolve in water, caused by ions migrating from the glass, and is supported by FTIR studies that indicate that the structure of the glass remains substantially intact through the manufacturing process (this is demonstrated through the presence of bands associated with Si-O bonds and the relative absence of those associated with the hydroxycarbonate apatite structure).

A number of advantages can be obtained by preparing the films from water soluble polymers, and an aqueous casting medium, as defined in the present invention. For example,

• Water soluble polymers dissolve / disperse rapidly in the mouth, providing a high concentration of bioactive glass, and therefore the ions required to form hydroxycarbonate apatite, on the surface of the tooth.

• Using an aqueous base (ie water soluble polymer) eliminates the need for expensive non-aqueous solvents, and the additional capital costs associated with solvent recovery or ensuring that the equipment is explosion proof.

• Solvents, even in small quantities, can cause irritation of the oral mucosa in sensitive individuals. Using only water reduces this risk.

• There are no environmental aspects with solvent emissions. 35

In accordance with an eighth aspect of the present invention, the use of a film as defined in any of the first, second, third, fourth and fifth aspects is provided to provide for remineralization of the teeth.

In accordance with a ninth aspect of the present invention, a method of treating teeth is provided by providing remineralization of the teeth using a film as defined in any of the first, second, third, fourth and fifth aspects of the present invention. .

Brief description of the drawings

Embodiments of the present invention will now be described, by way of example only, with reference to the accompanying drawings, in which:

Figure 1 shows the enamel hardening that results from the use of the four compositions (1 to 4) according to an embodiment of the present invention;

Figures 2a and 2b are MEB images of preformed white spot lesions, in accordance with an embodiment of the present invention;

Figures 3a and 3b are MEB images of enamel treated with a negative control film (composition 2) according to an embodiment of the present invention; fifty

Figures 4a and 4b are MEB images of enamel treated with a comparison Ml paste (composition 4) according to an embodiment of the present invention;

Figures 5a and 5b are MEB images of the enamel treated with the NovaMin composition of the present invention, in accordance with an embodiment of the present invention;

Figures 6a and 6b are MEB images of enamel treated with SootheRx for comparison (composition 3) according to an embodiment of the present invention.

Figure 7 shows an MEB image of an etched dentin surface;

Figure 8 is an MEB image of an etched dentin surface treated with a polymer film containing NovaMin in accordance with an embodiment of the present invention;

Figure 9 shows the comparison between a treated and untreated dentin surface; Y

Figure 10 describes in detail the results of an in vitro study regarding the effects of NovaMin-containing films on the growth of oral bacteria, which are associated with the development of caries and periodontal disease.

Brief Description of the Invention

Generally speaking, the present invention resides in the provision of a remineralization composition in the form of a film, which can adhere to one or more teeth, and provides a convenient and discrete method for generating a high local and sustained concentration of remineralizing components. on the surface of the 10 tooth. When hydrated, the film releases remineralization ions forming a layer of crystalline hydroxycarbonate apatite, stable on the surface of the tooth, providing a long-term reduction in tooth sensitivity. The film also has the ability to inhibit the growth of oral bacteria, associated with the development of caries and periodontal disease.

The film comprises a water soluble film former, such as a polymeric film former and a bioactive glass.

EXAMPLES

Surface Microhardness Tests

The results of the microhardness tests on the surfaces are shown in Figure 1. The results are presented as relative hardening of white spot lesions (for example, all data have been standardized for the measured hardness of the injured enamel). Treatment with 16% by weight of NovaMin film according to the present invention and 7.5% by weight of NovaMin toothpaste (SootheRx, positive control) resulted in significant hardening of the lesions of artificial white spots. Treatment with BioFilm control samples (negative control) and Pasta Ml (competitive product, contains Recaldent) does not change the surface hardening of the lesions. 25

MEB analysis

Figures 2a and 2b are scanning electrocardiography (SEM) images of white spot lesions in bovine enamel. Figure 2a is a low magnification view of the severe surface disruption that was caused by the formation of the lesion. Figure 2b is a high magnification image of the prismatic structure of the enamel that remained intact along the edges of the white dots and within the "bars" of the enamel 30 observed in Figure 2a. The images of the surfaces treated with BioFilm control samples (Figures 3a and b) and those treated with Paste Ml (Figures 4a and b) show the same characteristics.

Figures 5a-b are images of the injured enamel treated with 16% NovaMin BioFilm samples in accordance with the present invention. In a low magnification (Figure 5a) it is clear that a large amount of NovaMin particulate has been deposited on the surface of the lesions (especially along the edges). A view of greater magnification (Figure 5b) shows that the NovaMin particulate has adhered to the tissue and began to form a layer of persistent hydroxycarbonate apatite that is chemically similar to the tooth's native mineral and completely obscures the surface view of Injured enamel The images of samples treated with SootheRx (Figures 6a and b) show that treatment with a 7.5% NovaMin toothpaste produced very similar results. 40

Figure 7 shows untreated dentin with open tubules clearly visible. Figure 8 shows a similarly prepared dentin surface that has been treated with a simple application of a polymer film containing NovaMin particulate. It is evident that the polymer film has deposited bioactive glass on the surface of the dentin.

Figure 9 shows a piece of dentin that has been divided in two, the upper half treated with a polymer film containing NovaMin, and the lower part that remains untreated. The areas marked with green, yellow and orange color indicate where Novamin has been deposited.

Bacterial Growth Inhibition

The results of in vitro tests of films containing NovaMin particulate and their ability to inhibit the growth of oral bacteria are illustrated in Figure 10. Aqueous solutions of 1.0% NovaMin and 0.5 50% strips of Absorbable hydroxypropyl methylcellulose polymer containing 15% NovaMin. Six sets of 100%, 50%, and 25% serial dilutions of each solution were prepared, and 5 ml aliquots were inoculated with approximately 0.02 ml of Streptococcus mutans ATCC 25175, Streptococcus sanguinus ATCC10556, and Staphylococcus aureus NCTC 10418 Positive and negative controls were also prepared. All dilutions and test controls were incubated overnight at a temperature of 35 ° C and subsequently grated over 55

Tryptone Soy Agar Plates (TSA). Subsequently, the agar plates were incubated at a temperature of 35 ° C overnight and checked for growth. In total resistance (100%), 1.0% and 0.5% solutions completely inhibited the growth of the three bacterial species. The dilution of the solutions slightly decreased the inhibitory effect, although this was poorly compared to the control.

CONCLUSION 5

The results presented here indicate that a resorbable polymer strip containing 16% NovaMin particulate in accordance with the present invention (Test Product 1), has the potential to effectively treat white spot lesions that have formed on surfaces. of enamel. The treatment with the BioFilm samples containing NovaMin had an effect similar to the treatment with the toothpaste containing NovaMin (Test Product 3 - comparison) and, in this model, it worked largely better than the polymer-only absorbable strips 10 (Test Product 2) and toothpaste containing Recaldent (Test Product 4).

However, in a practical use it is expected that the film according to the present invention can remain in place in the tooth for a longer period of time than the toothpaste (comparison) which leads to a greater efficiency of remineralization fifteen

It has also been shown that a resorbable polymer product containing NovaMin has the potential to inhibit the growth of cariogenic and periodontal bacteria on tooth surfaces and adjacent gingival tissues.

Although specific embodiments of the present invention have been described above, it will be appreciated that departing from said described embodiments may still be within the scope of the present invention. For example, any type of soluble film former and bioactive glass can be used.

Claims (6)

1. A film for use in an oral cavity in which said film is produced from an aqueous mixture of its components and comprises: a water soluble polymeric film former that is an edible nonionic cellulose derivative selected from any one or a combination of methylcellulose, hydroxypropylmethyl cellulose, hydroxyethylcellulose, hydroxypropyl cellulose and carboxymethyl cellulose; and a bioactive glass comprising 40-80% by weight of silicon dioxide (SiO2), 0-35% by weight of sodium oxide (Na2O), 4-46% by weight of calcium oxide (CaO) and about 1 -15% by weight phosphorus oxide (P2O5); and wherein the bioactive glass is added to a solution of the polymeric film former to form the aqueous mixture and the bioactive glass is maintained in this aqueous environment for no more than 1-120 hours or more preferably 1-60 hours before that the water content be reduced by 5-70% by weight so as to minimize adverse reactions between the polymeric film former and the bioactive glass. 2. A film for use in an oral cavity according to claim 1, wherein said film is produced from an aqueous mixture of its components and wherein the water-soluble polymeric film former mixture 15 and The bioactive glass is passed through a high shear mixer to produce a homogeneous dispersion which in turn is deaerated before being coated on a conveyor paper and dried with air at a temperature higher than that of the environment. 3. A film for use in an oral cavity according to claim 1 or claim 2, wherein the edible non-ionic cellulose derivative is selected from hydroxypropylcellulose and hydroxypropylmethylcellulose. twenty 4. A film for use in an oral cavity according to claim 1 or claim 2, wherein the film comprises a water soluble polymeric film former in an amount of 1-90%, 20-80% , 30-70%, 40-80% or 50-60% by weight of the film. 5. A film for use in an oral cavity according to claim 1 or claim 2, wherein the particles that form the bioactive glass have an average particle size of less than 100 micrometers, less than 75 micrometers, smaller 50 micrometers, less than 20 micrometers, less than 10 micrometers, or less than 5 micrometers. 6. A film according to any one of claims 1 to 5 for remineralizing teeth.